Activity Transcript

Dr Amit Singal, MD, MS: Hello. I'm Amit Singal from University of Texas (UT) Southwestern Medical Center in Dallas, Texas. I want to welcome you to this exciting program entitled “Enhancing Equitable Care and Value-Based Practices: A Spotlight on Hepatocellular Carcinoma.” I have the pleasure of being joined by Aaron Jones, a nurse practitioner from Winship Cancer Institute at Emory Healthcare in Atlanta, Georgia. We have an exciting program for you today where we will discuss HCC across the entire spectrum from prevention to screening, to treatment, and really focus on how disparities impact each of these different steps.

Aaron, do you want to give us some basic information about HCC and why we should care about it?

Mr Aaron Jones, MSN, APRN, NP-C: Sure. I think this topic is very important. Hepatocellular carcinoma disproportionately affects racial, ethnic, and low-socioeconomic populations. There was a study in 2019 that showed racial and ethnic differences in outcomes are closely related with detection at an early stage and receipt of curative treatment. With these disparities in mind, we're going to explore some of the causes and modifiable risk factors as well as briefly touch on current treatment recommendations and the importance of collaboration within the healthcare team to overcome disparities.

Let's get started with a little background. Dr Singal, would you like to review the incidence and disparities in HCC for us?

Dr Singal: Aaron, when we think of HCC, it's really a global problem. When we look at this from a worldwide perspective, HCC is the third leading cause of cancer-related death. From a global perspective, we know that the highest burden for HCC resides in East Asia and in Africa, driven by high rates of endemic hepatitis B in those areas. In the United States, it has more of an intermediate incidence, but it's one of the few cancers that has a rising mortality rate. When you look at the top 10 cancers in terms of mortality from the Surveillance, Epidemiology, and End Results (SEER) registry, the mortality for most cancers is decreasing, and this is related to improvements in treatment over time, as well as improvements in early detection. But over the same time, liver cancer mortality has sharply risen and is one of the fastest increasing causes of cancer-related death here in the United States.

In fact, a recent study suggests that if these trends continue, HCC will become the third leading cause of cancer death here in the US. And so, this really highlights that this is the time where we need to think about HCC, how we can improve outcomes, how we can find this cancer earlier and how we can improve our treatment modalities to reduce mortality.

Now, when we think about this, there are several big issues with HCC. First, a minority of patients are found at an early stage, and as we'll talk about later, this really impacts our availability to deliver effective curative treatments. And the second is that despite improvements in treatment, the 5-year survival for HCC remains below 20%. Very few patients achieve 5- and 10-year survival. And so, this highlights that we need to do much, much better moving forward.

Finally, we know that HCC is unfortunately not evenly distributed across all demographics of the US. So, much like other health conditions and other cancers, there are notable disparities in both incidence and mortality. And like many other conditions, HCC disproportionately impacts racial and ethnic minority populations. So, when you look at this, the highest burden historically for HCC has been in Asian Pacific Islanders, this sort of population, we actually see improvements in HCC incidence and mortality, in part because improvements in hepatitis B vaccination and treatment programs, but we see marked increases in terms of HCC incidence and mortality among Hispanic populations and Black populations. And these incidence and mortality rates are much higher than what we observe in non-Hispanic Whites.

In addition to racial and ethnic disparities, we also see gender disparities where we see much higher incidence and mortality among men than women. And we also see socioeconomic status disparities, where we see higher incidence and mortality among communities with low socioeconomic status compared to high socioeconomic status communities. This really is related to differences in terms of HCC screening, differences in HCC early detection, as well as differences in treatment utilization. And I think those will be some of the concepts that we will talk about further through this webinar.

Aaron, one of the key things that I think that we both recognize is the fact that the strongest risk factor for HCC is the presence of underlying cirrhosis. Over 80 to 90% of patients who develop HCC do so in the setting of cirrhosis, and this is found at the time of diagnosis. But cirrhosis can happen from many etiologies, whether that's viral in nature or nonviral etiologies. How do you think these differential risk factors contribute to the disparities that we see in HCC incidence and mortality?

Mr Jones: Well, Dr Singal. I know there're some studies showing that about 70% of liver cancer cases in the US could potentially be prevented through the elimination of some risk factors. One of those is excessive body weight. Another is type 2 diabetes, chronic infection with hepatitis B and C, heavy alcohol consumption, tobacco smoking. There are a lot of things that we can do to work on decreasing the risk for HCC overall. Heavy alcohol consumption they say is 3 or more drinks per day per some studies. So, education for the general public, as far as decreasing these risk factors can go a long way.

Another thing that I'm curious to get your opinion on is some metabolic disorders that can come along with decreasing risk. There are things such as hereditary hemochromatosis or porphyria cutanea tarda, alpha-1 antitrypsin deficiency, Wilson's disease. These are other metabolic disorders. Are we looking at these across the board for decreasing the risk for HCC in some populations?

Dr Singal: Aaron, when I think of HCC and I think of the underlying etiologies for cirrhosis, historically the most common etiologies for liver disease and HCC have been viral in nature. The most common risk factor globally has been hepatitis B. The most common risk factor in the Western world, including Western Europe and the United States has been chronic hepatitis C. When we think of those risk factors, we see nice decreases into those underlying etiologies. This is related to implementation of hepatitis B vaccination programs, hepatitis B antiviral treatments and highly effective hepatitis C antiviral treatments that can result in cure. So, you can treat someone for hepatitis C with an 8- to 12-week oral regimen, and essentially cure them of their hepatitis C, reducing their HCC risk somewhere between 75 to 95% in those individuals.

In addition to those viral etiologies, we see a large proportion now being due to nonviral etiologies. The 2 most common nonviral etiologies are alcohol-associated cirrhosis and nonalcoholic fatty liver disease. And so, nonalcoholic fatty liver disease is the liver manifestation of the metabolic syndrome. So people who have obesity, diabetes, they can have fat deposits in their liver that can cause chronic inflammation, cirrhosis, and those patients can have an annual risk of developing HCC.

Now, these other risk factors that you mentioned, alpha-1 antitrypsin, Wilson's disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), these all can cause cirrhosis, and they do have a risk of developing HCC, but they contribute a relatively small amount in terms of the proportion of HCC cases. The 1 genetic cause that you mentioned, hemochromatosis, is interesting. This is one of the more common genetic mutations in Caucasians, and has a very high risk of developing HCC, but just overall, once again, contributes a small proportion of HCC cases worldwide.

Now, when we think of disparities, thinking through these different etiologies is very interesting and very informative. Historically for example, chronic hepatitis C cases were higher among Black communities than they were among Hispanic communities and Caucasian communities. In contrast, the other risk factors like nonalcoholic fatty liver disease are more common among Hispanic communities than they are among Black and White communities. These disparities are related to many different causes, some of them being environmental, some of them being genetic - for example, Hispanics having some genetic risk factors for fatty liver disease, including PNPLA3/rs7. There're these genetic risk factors that make them predisposed to develop fatty liver disease, as well as develop HCC in the setting of fatty liver disease. But the reason why these are fascinating is as you think through the epidemiology of HCC moving forward, you're talking about hepatitis C-related HCC decreasing in prevalence and the proportion of HCC related to alcohol and nonalcoholic fatty liver disease increasing.

We may see differing impact on different racial and ethnic and socioeconomic groups as we move forward. And so, these disparities, I don't think they're going to get any smaller, but will be shifting over time as we see changes in risk factors over time.

Aaron, I think that, obviously there's a lot that we need to do in terms of addressing collaborations. Can you discuss how the healthcare team should come together in terms of thinking through how we can start to address disparities?

Mr Jones: Sure. Now, obviously we know, even just from a day-to-day practice, that we can see some healthcare disparities across the board, patients not being able to make it to the clinic due to transportation issues or lack of finances or a number of reasons. I did review the Institute of Medicine's guidelines. They created some recommendations to discuss disparities in healthcare. The big categories for that were just general recommendations. They also discuss policy interventions, health system interventions, patient education recommendations, cross-cultural education recommendations and data collection.

Some of the big points that I find interesting are increasing awareness among the public regarding disparities, increasing awareness among healthcare providers, implementing patient education programs, and integrating cross-cultural education into the training among current and future healthcare professionals. Also, I think we should continue to collect and report on healthcare access among this population.

I think that it's important to also discuss the impact of primary care outreach and having a good relationship with primary care physicians who are on the front lines of screening for cirrhosis and hepatitis B and C. I think increasing awareness as a whole, for this population can be beneficial, as we know that early detection of HCC can improve overall outcomes for these patients. I think as a healthcare team, better communication and building relationships between hepatology, gastroenterology, and a primary care physician, a faster referral to hepatology in patients at risk, or who have been identified to have cirrhosis and improving screening and healthcare trust among the high-risk groups.

I wanted to talk a little bit about preventative techniques to address healthcare disparities in HCC. The first thing I'd like to discuss is primary prevention, and this includes lifestyle modification. There is some research looking at the Mediterranean diet that reduces the risk of developing HCC as well as increase in polyunsaturated fatty acids, increase in white meats, including fish and poultry, consuming more vegetable oil and fiber, and decreasing the consumption of red meats, saturated fats, and cholesterol. Other modifiable risk factors include exercise. There is a positive association between being overweight and obese and increased risk for HCC. Smoking. . . . this can also lead to liver fibrosis and HCC, and has a synergistic effect with alcohol consumption, according to a study.

Other primary prevention techniques that can be used are managing the chronic viral infections such as getting the hepatitis B vaccine, chronic management of hepatitis B infection, and treatment of hepatitis C infection. Dr Singal, would you like to comment on the primary prevention and then discuss the secondary prevention?

Dr Singal: Aaron, I think you touched upon several aspects of primary prevention, which can, if effectively implemented help reduce HCC incidence. As I referenced before, really, the management of viral hepatitis is one of the most effective chemoprevention efforts that we can do in terms of reducing HCC.

In addition to primary prevention, there's a lot of emphasis on secondary prevention. So secondary prevention really is HCC screening in hopes of finding the cancer at an early stage so we can deliver effective curative treatments and thereby reduce mortality. There's been several cohort studies showing a consistent association between the receipt of HCC screening and improved clinical outcomes, including increased early detection, as well as reduced mortality. There is a nice meta-analysis that we recently published in the Journal of Hepatology, summarizing these cohort studies and the associations with these improved clinical outcomes. These data have underlined the recommendations from several professional societies, including the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the National Comprehensive Cancer Network, all these societies recommend HCC screening in at-risk patients, including those with cirrhosis. Screening, relatively simple, you use an abdominal ultrasound and a blood test called alpha-fetoprotein. This should be done on a semiannual basis.

Unfortunately, despite the relatively easy nature of the HCC screening tests and the targetable at-risk population, HCC screening is unfortunately vastly underused in clinical practice. So, compared to other cancers like colon and breast cancer, where those cancer screening programs are done in 60 to 70%, if not higher, of at-risk individuals, HCC screening is performed in less than 25% of at-risk patients with cirrhosis. So clearly, we need to do better.

Once again, going to this theme of disparities, there is a study that was published a few years ago from a large safety net institution that shows lower screening utilization among African Americans, as well as underinsured individuals compared to their counterparts. Once again, racial, ethnic, and socioeconomic disparities in terms of HCC screening, which then contributes to disparities in early detection. These low rates of HCC screening are being addressed through many intervention studies as part of a systematic review that was published a couple years ago. There was a nice summary of multiple interventions that had been tried, whether those were "in-reach efforts" using things like provider education, patient education, or electronic medical reminder systems, or outreach systems where you can mail patients a letter that invites them to get the screening done. These interventions have been shown to be effective across the board, but we just need to do better in terms of implementing these as part of routine clinical care.

Now, the importance of these interventions are numerous, but really, these interventions address many reported patient and provider barriers to performing HCC screening. There was a study that was done among patients a couple years ago from 3 different health systems, a safety net health system and academic system, and a Veterans Affairs health system, and patients across those 3 different health systems, all reported notable barriers to getting HCC screening done, including financial barriers, transportation barriers, and difficulties logistically scheduling the ultrasound. Similarly, a study among primary care providers from 2 academic institutions found providers also report barriers, most notably limited time in clinic, competing interests in that short period of time. And so, these intervention studies are going to be very important as we address those identified patient and provider barriers.

Now, Aaron, that's really the high-level overview of primary and secondary prevention, but of course, one of the other big aspects of the cancer care continuum is actual treatment. As you know, exciting time to treat HCC. We've seen dramatic improvements across the board in terms of HCC treatments. When I think of HCC treatment, I think of dividing this into 4 different buckets. We have our treatments for early stage, we have our treatments for liver localized intermediate stage, and then we have our treatments for advanced stage. Those buckets are starting to break down where we're starting to see combinations and stage migration, but those are the sort of simple high-level overview buckets that I like to think about in my mind.

When I think of the therapies that we have for patients that are found at an early stage, the most effective therapies that we have are surgical in nature. If somebody has good liver function, limited tumor burden, one of the best therapies that we can do is surgical resection, where you go in, you remove the HCC and you can achieve 5-year survival rates exceeding 60%. Now, one of the limitations of surgical resection is you leave behind that liver that typically has cirrhosis. And so, the recurrence rates are high, recurrence rates exceed 50% within 5 years.

Now, in contrast, if somebody has under underlying liver dysfunction, so is not child Pugh A, but has signs of portal hypertension, or has more than 1 liver lesion, but still has early-stage disease typically within the United Network for Organ Sharing (UNOS) downstaging criteria, those patients are best treated with liver transplantation, a cure for the HCC as well as the underlying cirrhosis. Five-year survival rates succeed 70%, and this has the lowest chance of recurrence. So, a 5-year recurrence rate is somewhere around 10%. This is an excellent therapy. The only limitation of liver transplantation is the limited grafts that we have available on a national scale, so we have to be thoughtful of which patients we transplant vs deliver other therapies.

If you're found in an early stage, typically, a lesion less than 3 cm and are not eligible for these curative therapies for one reason or another, then you can be treated with local ablation. Historically, this is done by radiofrequency ablation. More and more sites are using microwave ablation. You're typically able in lesions less than 3 centimeters, able to offer complete responses in about 95 to 97% of patients.

Moving on to that bucket, so if you have liver-localized disease, but beyond an early stage, that we typically think of embolic therapies. So, you think of doing chemoembolization or radioembolization, where you selectively target the blood supply to the HCC, you inject beads with either chemotherapy or radiation therapy, treat the tumors locally, able to induce responses in a high proportion of patients, but these are typically not regarded as curative. In the advanced stage setting, we really have seen a tremendous advance in terms of the available systemic therapies that we have available.

Just over 10 years ago, we had the first systemic therapy that was shown to have a significant survival benefit for advanced HCC sorafenib, first tyrosine kinase inhibitors that was shown to improve overall survival in this setting. Over the next 7 to 8 years, if not a decade after the SHARP trial where sorafenib was approved. We unfortunately had nothing. That was the only therapy that was still shown to be a benefit. But the last couple years have been really an exciting time where we've seen several agents come to market. Multiple other tyrosine inhibitors for these targeted therapies acting on different cancer pathways are showing a benefit in the first line, second line, and even 1 agent in the third-line setting. And then most recently, we've seen the advent of immunotherapy. So just like immunotherapy has revolutionized other cancers, it's significantly improving survival for patients with advanced-stage HCC, where we now see a median survival of 19 months for patients with advanced-stage HCC.

So, the combination of atezolizumab and bevacizumab was the first immunotherapy that was shown to improve survival compared to sorafenib. More recently, the HIMALAYA trial presented data under durvalumab and tremelimumab, 2 immunotherapy agents used together a programmed cell death protein 1 (PD-1) and a cytotoxic T-lymphocyte-associated protein 4 (CTLA4), where they basically in combination also improve survival compared to sorafenib. And so, we're starting to see dramatic improvements, even in our palliative therapies for HCC.

Now, going back to the disparities angle of this, while we've seen advances in the treatment side, one of the key things is that there unfortunately continues to be disparities in treatment allocation. And this has been particularly shown on the early-stage side. Several studies have shown that racial/ ethnic minorities, including Blacks and Hispanics, are less likely to undergo curative therapy, even when found at an early stage. We talked about disparities in the screening, disparities in early detection. And so even as you move down, if you're found at an early stage and level the playing field, there's still disparities in treatment receipt. And so, this is really once again, one of the things that we need to do better on as we move forward.

So, Aaron, thinking through this, in terms of disparities that each of these healthcare delivery aspects, what do you think we can do to improve these disparities? How can we engage patients?

Mr Jones: Dr Singal, I think patient engagement is very important. One study in particular looked at newly diagnosed patients with HCC, and common barriers that were reported were time commitment to undergo treatment, uncertainty regarding their HCC diagnosis, doubts about the necessity of treatment, concern regarding paying bills. That was consistent across all races that were asked.

And in this study, it was interesting that Black patients were more likely to report any of these barriers compared to White and Hispanic patients. There's a high level of medical mistrust, and that was higher among the Black population than Whites or Hispanic in this study. Access and transportation are also kind of a key barrier. And I think that it's important to look at these key barriers and try to create interventions to correct them because they are associated with poor prognosis in this patient population.

I think overall, what I have seen work in my practice, which may not be the same as you or at other institutions includes community education, increasing awareness of these barriers for patients and providers. I am fortunate to have a social worker, but in getting social workers involved to help provide transportation access to be able to obtain care, direct communication between the providers, including a pharmacy team at times, or nursing team to help continue the education process for these patients, reviewing diagnosis and treatment plans up front and in plain English or their primary language with the translator. I am lucky as well in the sense that I have a financial counselor, but making sure that there's access for patients to be able to understand their bills and how they will be billed.

I think 1 other way to kind of help continue to engage with the patients and decrease these barriers are to consolidate care. For me specifically, we have patients that travel hours and hours to get to us, and that can be very difficult. So, minimizing the amount of times that they have to come to the clinic may be beneficial. Another emerging topic is the multidisciplinary clinic that is becoming more prevalent. That's something that might be seen at bigger academic institutions, but it's not always available everywhere.

I think that if patient engagement improves and we can have more frank discussions and more education, we can decrease these help disparities and hopefully decrease mortality overall. One question that I would like to kind of pose or discuss is, how can the healthcare team collaborate effectively to engage with the patients? And I do think that early detection is key, screening processes with primary care physicians and then referral to gastrointestinal (GI) or hepatology. Some of that actually includes the nurse practitioner/physician assistant (PA) role in expanding access to care for patients in rural areas and having a good relationship with those providers, with medical oncologists, throughout the region.

Dr Singal: Aaron, a lot of excellent points that you had there. So clearly, many of these barriers need to be addressed. And there's a lot that I think healthcare teams can think through in terms of how we can address these different barriers.

I'm just going to highlight a couple things that you brought up that I think are worth explicitly mentioning. The first is that the healthcare team extends beyond physicians and advanced practice providers (APPs). And so, when we think of the healthcare team, it's important to remember that this really includes nurses, social workers, et cetera. And those extenders really are quite important when you're engaging patients. They can work through many of these barriers. They can work through financial barriers, social barriers, and they can really serve as a conduit to have continual education and engagement with the patient that can reduce many of these barriers like medical mistrust, address health literacy, as we move forward.

The other thing is, as we start to have a growing part of the US be of Hispanic and maybe Spanish speaking, I think it's more and more important that we start to have educational materials, not just available in English. We need these materials translated into multiple different languages, so they can speak to the patient in their preferred language. Once again, getting over health literacy. We talked about HCC at its highest level and struggle to do so in 30 minutes. This is a complex cancer where it's a disease within a disease. And the only way that you can do this is if you really work with the patient on a level that they feel comfortable. I think really having multicultural, multilanguage educational materials is going to be very important as we try to engage patients so they feel comfortable with this.

The other thing is that you talked about transportation barriers, which we know exist. And I think that you brought up 2 important things that can help address this. The first, we've all become very used to doing everything virtual. And so, virtual visits, it took me a little bit to get used to it, but now I'm used to it. And I think it's going to be a part of our clinical practice that has benefits, particularly as we start thinking through individuals that live in rural America and have to travel 3 hours to get to their clinic visit or need to arrange childcare or take off time off work. If you're able to shrink a 2-hour engagement of driving to the healthcare system, doing the visit, and driving back to a 30-minute clinic that one can do on their phone or their computer, that dramatically helps patients.

Then you also talked upon the multidisciplinary format. At UT Southwestern, we've actually had colocated clinics for now about 7 or 8 years. We were one of the first clinics to adopt a colocated clinic where we had multiple providers available to a patient. It's a 1-stop shop. So instead of patients being referred to see hepatology who then refers them to see a surgeon, get an opinion from an interventional radiologist, et cetera, the idea of our clinic is that we have it, so the physicians are traveling to the patient. So that patient comes in and they see the providers that they need to see. It minimizes the number of engagements they need to do. And thereby, you would do some of these logistical barriers and you can make it, so patients receive the care they need. And part of that, the hepatologist is the transplant hepatologist. So is not only taking care of that patient's liver function as they go through therapy, but also considering liver transplantation.

And I think these kinds of clinics are going to become more and more important as we think through combination therapies, as well as stage migration, where you can have decreases or increases in tumor burden and thereby have to consider other therapies moving forward. So, lots of issues that exist in terms of disparities, but lots that we can think through and implement as we move forward.

Aaron, I think that brings us to time. I really want to thank you for joining me in this discussion. I think that for our listeners at home or viewers at home, I think there are a few different things that I think are worth taking home with you today. The first, HCC is a cancer that if you haven't heard of it before, you should hear of it now. This is a cancer that's rising in terms of mortality, and it's going to become only more and more common in terms of your clinical practice. Two, there are effective primary and secondary prevention mechanisms that we can do to reduce mortality, including antiviral treatments for at-risk individuals and screening at-risk patients, including those with cirrhosis, using semiannual ultrasound and alpha-fetoprotein to help identify patients with HCC early.

Three, we have an expanding arsenal of therapies that we have available for HCC patients, including surgical therapies for early-stage disease, surgical resection, liver transplantation cures. We have expanding local, regional, and systemic therapies that are improving prognosis for patients who are not amenable to surgical therapies. This is no longer a death sentence. We have very effective therapies across the stage spectrum. Finally, once again, we've discussed this several times, this is a disease that doesn't proportionally impact all patients. And unfortunately, there continues to be disparities, not only in incidence but also mortality. And as Aaron and I talked about, this is due to several different barriers, several different reasons. There are things that we can do as a healthcare team, and we should do as a healthcare team to not only reduce HCC mortality overall, but also reduce HCC disparities and move to a health equity model in the future. So hopefully, we can all work together and make that dream a reality for HCC.

Once again, I want to thank Aaron for joining me today. I want to thank you for participating in this activity and watching the last half an hour about HCC and disparities. Please continue and answer the questions that follow and complete the evaluation for our program. Once again, thank you so much.

This transcript has been edited for style and clarity.